Omeprazole process impurities and preparation method thereof
A process impurity, omeprazole technology, applied in the field of medicine, can solve the problems of difficult quality research, clinical drug safety monitoring, separation, structure confirmation and synthesis preparation, and difficult source of drug impurity reference substances, so as to achieve perfect quality The effect of standards and controls, easy operation, and mild reaction conditions
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Embodiment 1
[0049]Example 1 Generation, separation and identification of impurities
[0050]In this example, the omeprazole intermediate 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride was prepared by referring to the method in patent US4544750A.
[0051]Step A: Synthesis of Compound A:
[0052]
[0053]Take 3,5-dimethyl-4-methoxypyridine nitroxide (35.9g, 0.235mol) in a single-neck flask, add 145mL chloroform and stir to dissolve, heat up to 60℃, and add dimethyl sulfate (24.4mL , 0.258mol), turn off the heating after 5 hours to stop the reaction. Cool down, add water for extraction, and evaporate to dryness to obtain 65.0 g (23.29 mmol) of compound A as a solid, with a yield of 99.1%. Common nuclear magnetic map such asfigure 1 Shown.
[0054]Step B: Synthesis of Compound B
[0055]
[0056]Take compound A (4.9 g, 17.56 mmol) and add 20 mL of methanol, stir to dissolve uniformly, and heat to reflux. Ammonium persulfate solution (4.01g, 17.57mmol, ammonium persulfate dissolved in 7.5mL water) was added...
Embodiment 2
[0077]Example 2 Preparation of Impurity I
[0078]
[0079]Take 1 g of 3,5-dimethyl-4-methoxypyridine nitrogen oxide and place it in a three-necked flask, add 0.2 mL of chloroform and 0.5 mL of water to dissolve, and slowly add 0.68 mL of dimethyl sulfate dropwise. Under argon protection, react at 80°C for 3h.
[0080]Post-treatment: the reaction solution obtained above was cooled to room temperature, and 4 mL of water and 4 mL of chloroform were added for extraction. The organic phases were combined and spin-dried. DCM:MeOH=20:1 (volume ratio) column chromatography to obtain impurity I.1H NMR(300MHz, CDCl3)δ7.46(s,2H),4.00(s,3H),2.05(s,6H).HRMS(ESI,M / Z):Calculated for[M-X]+:154.09,[M-X-H+Na]+: 176.07, found: 154.0859, 176.0683.
Embodiment 3
[0081]Example 3 Preparation of Impurity III
[0082]
[0083]ZrCl4(815mg, 3.5mmol) was dissolved in dry tetrahydrofuran (35mL), and NaBH was added in batches at room temperature under nitrogen atmosphere4(500mg, 13.2mmol). After stirring for 10 minutes, reaction solution A was obtained; 3,5-dimethyl-4-methoxypyridine nitroxide (500mg, 3.3mmol) was dissolved in dry tetrahydrofuran (15mL) , The reaction solution B is obtained; the reaction solution B is added to the reaction solution A at 0-5° C., the temperature is raised to room temperature, and the reaction is stirred. TLC monitors the progress of the reaction. After the reaction was completed, it was cooled to 0°C, and dilute hydrochloric acid was added dropwise to quench the reaction. The tetrahydrofuran was distilled off under reduced pressure, the aqueous layer was extracted with ethyl acetate (30 mL×3 times), and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase...
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